Project Summary/Abstract There is mounting evidence that low vitamin D blood levels are associated with increased risk of dementia and Alzheimer's disease (AD). There are several mechanisms by which low vitamin D status may promote AD pathology, including reduced ?-amyloid (A?) clearance, dysregulation of calcium influx and glutamate- mediated neurotoxicity. Vitamin D interacts with receptors in the hippocampus and many other brain regions, and has established antioxidant and anti-inflammatory effects. Recent neuroimaging studies have found that low vitamin D levels are associated with increased periventricular white matter disease, reduced white matter volume and larger ventricles. Vitamin D deficiency may also have a toxic effect on brain function independent of A? metabolism. Preliminary studies of serum vitamin D levels in a diverse multi-ethnic cohort (n=382) of the UC Davis Alzheimer's Disease Center found a high prevalence of low vitamin D status (61% with levels <20 ng/ml), which was associated with faster rates of decline on executive function and episodic memory. This Phase II randomized clinical trial aims to test if supplementation with high dose oral vitamin D will successfully correct vitamin D insufficiency, compared to treatment with standard (RDA) dose vitamin D in a diverse community-based elderly cohort. The effect of high-dose vs. standard-dose vitamin D on altering cognitive trajectories will also be assessed and data will be expected to be used in designing a potential definitive Phase III trial in elderly groups at risk for dementia. A total of 180 elderly persons with longitudinal biomarkers, neuropsychological testing and brain MRI scans will be enrolled, with 152 (~50 with MCI, 50 with mild AD and 50 with no cognitive impairment) expected to complete the 3-year study. One-half of each diagnostic group will be randomized to treatment with high-dose vitamin D3 (4,000 IU daily) or to standard dose Vitamin D (600 IU capsule daily + ~200 IU dietary = ~800 IU total/day). Longitudinal MRI analyses will provide an estimate of the treatment effect size on brain atrophy rate. Vitamin D receptor genotype polymorphisms and their impact on response to oral supplementation will also be examined. If vitamin D supplementation improves cognitive outcome, this could have a large impact on the public health, since low vitamin D status is a common, readably treatable condition which may provide a novel window to prevent dementia and AD. Furthermore, the higher prevalence of AD and dementia in African Americans and Latinos could be partially attributable to vitamin D insufficiency.